JPH11512736A - Stable composition containing N-propargyl-1-aminoindan - Google Patents

Stable composition containing N-propargyl-1-aminoindan

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JPH11512736A
JPH11512736A JP9514119A JP51411997A JPH11512736A JP H11512736 A JPH11512736 A JP H11512736A JP 9514119 A JP9514119 A JP 9514119A JP 51411997 A JP51411997 A JP 51411997A JP H11512736 A JPH11512736 A JP H11512736A
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pharmaceutical composition
propargyl
composition according
aminoindan
alcohol
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JP4108750B2 (en
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バーガー・ペスキン、タートサー
カチウラル、ファニー
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テバ・ファーマシューティカル・インダストリーズ・リミテッド
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

(57)【要約】 活性成分としてラセミ体、Ｓ（−）、及びＲ（＋）−Ｎ−プロパルギル−１−アミノインダン又はこれらの薬学的に許容しうる塩、及び少なくとも６０重量％の、少なくとも１つの五価及び六価アルコールを含有する薬学的組成物。該組成物は、任意に、クエン酸及びステアリン酸マグネシウムを含有しうる。   (57) [Summary] Racemic, S (-) and R (+)-N-propargyl-1-aminoindan or pharmaceutically acceptable salts thereof as active ingredients and at least 60% by weight of at least one pentavalent and hexavalent Pharmaceutical compositions containing a polyhydric alcohol. The composition may optionally contain citric acid and magnesium stearate.

Description

【発明の詳細な説明】 Ｎ−プロパルギル−１−アミノインダンを含有する安定な組成物 発明の分野 本発明は、ラセミ体、Ｓ（−）又はＲ（＋）エナンチオマーのＮ−プロパルギ ル−１−アミノインダンの製剤、特にエナンチオマーＲ（＋）のＮ−プロパルギ ル−１−アミノインダン（以後、Ｒ（＋）ＰＡＩと称する。）であって、例えば パーキンソン症の治療に使用されるＢ−型の酵素モノアミンオキシダーゼの選択 的な不可逆的阻害剤であるものの製剤に関する。以下では、酵素モノアミンオキ シダーゼをＭＡＯと称し、そのＢ−型をＭＡＯ−Ｂと称する。 発明の背景 ＧＢ 1 003 686 には、ベンゾシクロアルカン化合物であって、シクロアルカ ンが５から７員環を有し、Ｎ−（アルキニルアルキル）アミノ基で置換されてい るものの一群、及びＭＡＯ阻害剤としてのこれらの使用が開示されている。該特 許には更に、ベンジルアルコール、ステアリルアルコール、及びメタノールのよ うな種々のアルコールを含めた種々の基質と混合した主題化合物の使用が開示さ れている。しかし、該特許は、製品の安定性の問題を回避するように、何れの多 くの可能な担体及び他の成分をどのように選択するか、及びいかなる基準で選択 するかを教示していない。 本発明の目的は、効果的な量の、ラセミ体、Ｓ（−）又はＲ（＋）−Ｎ−プロ パルギル−１−イルアミノインダンを含有する安定な製剤を提供することにある 。簡略化のために、特に断らない限り、略称ＰＡＩを、Ｎ−プロパルギル−１− アミノインダンのエナンチオマー、並びにこれらのラセミ混合物を表すのに使用 する。 本発明の概要 本発明によれば、驚くことに、ＰＡＩを含有する製剤の安定性は、かなり大量 の特定のアルコールを取り込むことによって十分に改善されうることが見出され た。 本発明によれば、活性成分として、ラセミ体、Ｓ（−）、及びＲ（＋）−Ｎ− プロパルギル−１−アミノインダンの群から選択される構成要素である化合物又 はこれらの薬学的に許容しうる塩の治療に効果的な量、及び少なくとも６０重量 ％の、五価又は六価アルコールの群から選択される構成要素である少なくとも１ つのアルコールを含有する薬学的組成物が提供される。 本発明の好ましい態様では、活性成分はＲ（＋）−Ｎ−プロパルギル−１−ア ミノインダンである。 好ましくは、組成物は少なくとも７０％の前記の少なくとも１つのアルコール を含有する。 典型的には、本発明に従って使用されるアルコールは、マンニトール、キシリ トール及びソルビトールの群から選択される構成要素である。 本発明によれば、ＰＡＩを含有する組成物は、クエン酸を、好ましくは０．５ から２重量％の量で更に含有しうる。 所望であれば、本発明に従った組成物はステアリン酸マグネシウムを、好まし くは０．１から０．５重量％の量で更に含有しうる。この態様によれば、前記少 なくとも１つのアルコールの量が７０重量％以下である場合、組成物は更に、ク エン酸を先に明記した量で含有する。前記少なくとも１つのアルコールの量が少 なくとも７０重量％である場合、クエン酸の含有は任意である。 本発明の組成物はまた、フィラー、潤滑剤、崩壊剤、滑翔剤（glidants）、調 味剤、甘味料、着色剤等（全て、それ自身公知である。）のような従来の添加剤 を任意に含有しうる。本発明に従って使用しうるフィラーの例は、ラクトース、 デンプン、微結晶性セルロース、マルトリン等である。 本発明の組成物は、当業者によく知られているそれ自身公知の方法で調整され る。例えば、ＰＡＩ及び全ての他の活性成分（潤滑剤を使用する場合は、これを 除く。）をふるいにかけ、適切な顆粒形成機中で完全に混合する。顆粒化は、純 水の存在下で行うことができ、引き続いて組成物を乾燥する。次に、乾燥した顆 粒を粉砕し、滑化し、錠剤に圧縮する。Ｒ（＋）ＰＡＩ自身は、例えばＷＯ95/1 1016 の例６Ｂに開示された方法に従って調製されうる。 以下の非制限的な例を例示の目的で示す。 例 例１ mg/錠剤 Ｒ（＋）−Ｎ−プロパルギル−１−アミノインダンメシレート 3.12 マンニトール 62.5 マルトデキストリン（マルトリン１５０） 36.0 クロスカルメロースナトリウム （Ｃroscarmellose sodium）（Ａc-Ｄi-Ｓol） 2.1 タルク 1.5 例２ mg/錠剤 Ｒ（＋）−Ｎ−プロパルギル−１−アミノインダンメシレート 1.56 マンニトール 79.14 デンプン 10.0 予めゼラチン化されたデンプン 10.0 コロイド状二酸化ケイ素 0.6 タルク 2.0 ステアリン酸 2.0 例３ mg/錠剤 Ｒ（＋）−Ｎ−プロパルギル−１−アミノインダンメシレート 3.12 マンニトール 76.58 デンプン 10.0 予めゼラチン化されたデンプン 10.0 コロイド状二酸化ケイ素 0.6 クエン酸 1.0 タルク 2.0 例４ mg/錠剤 Ｒ（＋）−Ｎ−プロパルギル−１−アミノインダンメシレート 3.12 マンニトール 69.88 ラクトース（含水） 14.0 デンプン 14.0 グリセリルベヘネート（コンピトロール８８８ＡＴＯ） （Ｇlyceryl Ｂehenata）（Ｃompitrol 888ＡＴＯ） 2.0 例５ mg/錠剤 Ｒ（＋）−Ｎ−プロパルギル−１−アミノインダンメシレート 3.12 マンニトール 77.28 デンプン 10.0 デンプンＳＴＡ−ＲＸ １５００ 10.0 コロイド状二酸化ケイ素、エアロシル 0.6 水素化ベジタブルタイプＩ（ステロテックス ドライテックス） 2.0 例６ 本発明の組成物と、従来技術で公知のものとを比較するために、上記製剤の２ つをＷＯ95/11016に開示された製剤と比較した。ＷＯ95/11016の製剤 mg/錠剤 Ｒ（＋）−Ｎ−プロパルギル−１−アミノインダンＨＣｌ 1.56 ラクトース（含水） 50.0 予めゼラチン化されたデンプン 36.0 微結晶性セルロース 14.0 ナトリウムデンプングリコレート 2.14 タルク 1.0 ステアリン酸マグネシウム 0.5 この製剤、並びに本出願の例２及び３で説明した製剤を、６ヶ月間４０℃、７ ５％湿度にさらした。活性成分の分解物の割合を６ヶ月の期間の最後に検定した 。 以下の手順を調製された製剤の分解を決定するために適用した。錠剤を細かく 粉末化し、水、アセトニトリル及び過塩素酸の混合物のような希釈剤で抽出した 。抽出生成物のアリコートを、ＨＰＬＣに注入し、前記希釈剤混合物と同様の混 合物を用いて溶出した。ＰＡＩ化合物に対応する領域を何れかの他の主要ピーク の領域と共に測定した。分解の割合の計算は、標準の調製物から得られる領域と 測定したピークの領域を比較することで行った。 ＷＯ95/11016 の例２０の開示に従って調製された製剤は、貯蔵後に３．０８ ％の分解物を含有していたが、例２及び例３の組成物は、それぞれ、０．５１％ と０．１％以下の分解物を含有していた。 例７ 本発明に従った製剤及び ＷＯ95/11016 の例２０の説明に従った他の製剤は、 表１に示した成分を含有するように調製した。この表に示される製剤を、ＷＯ95 /11016 の開示に従って調製した場合、「ＰＣＴ」と表わし、数字で表される製 剤は、説明した本出願の例の数字に対応する。幾つかのこれらの略称の次に現れ る修飾記号Ａ、Ｂ、Ｃ又はＤは、前記製剤の特定の変更を表す。表２に示される 分解の割合は、７５％湿度で、５５℃で１ヶ月又は４０℃で６ヶ月間これらを保 存した後、表１の製剤の全てに対して計算した。後者の保存条件に従って保存さ れたこれらの製剤は、アスタリスク（*）で表中にマークした。表２からわかる ように、本発明の全ての組成物の安定性は従来技術のものよりも優れている。 Description: FIELD OF THE INVENTION The present invention relates to a racemic, S (-) or R (+) enantiomer of the N-propargyl-1-amino enantiomer. Formulations of indane, especially the enantiomer R (+) N-propargyl-1-aminoindan (hereinafter referred to as R (+) PAI), for example the monoamine of the B-type enzyme used in the treatment of Parkinsonism It relates to the preparation of those which are selective irreversible inhibitors of oxidase. Hereinafter, the enzyme monoamine oxidase is referred to as MAO, and its B-form is referred to as MAO-B. GB 1 003 686 discloses a group of benzocycloalkane compounds, wherein the cycloalkane has a 5- to 7-membered ring and is substituted by an N- (alkynylalkyl) amino group, and a MAO inhibitor The use of these as is disclosed. The patent further discloses the use of the subject compounds in admixture with various substrates, including various alcohols such as benzyl alcohol, stearyl alcohol, and methanol. However, the patent does not teach how to select any of a number of possible carriers and other ingredients, and on what basis, so as to avoid product stability issues. It is an object of the present invention to provide stable formulations containing an effective amount of racemic, S (-) or R (+)-N-propargyl-1-ylaminoindan. For simplicity, the abbreviation PAI is used to denote the enantiomer of N-propargyl-1-aminoindan, as well as the racemic mixtures thereof, unless otherwise specified. SUMMARY OF THE INVENTION In accordance with the present invention, it has surprisingly been found that the stability of a formulation containing PAI can be significantly improved by incorporating significant amounts of certain alcohols. According to the present invention, the active ingredient is a compound which is a component selected from the group of racemic, S (-), and R (+)-N-propargyl-1-aminoindan, or a pharmaceutically acceptable compound thereof. Provided is a pharmaceutical composition comprising a therapeutically effective amount of a possible salt and at least 60% by weight of at least one alcohol which is a component selected from the group of pentahydric or hexahydric alcohols. In a preferred embodiment of the present invention, the active ingredient is R (+)-N-propargyl-1-aminoindan. Preferably, the composition contains at least 70% of said at least one alcohol. Typically, the alcohol used according to the present invention is a component selected from the group of mannitol, xylitol and sorbitol. According to the invention, the composition containing PAI may further contain citric acid, preferably in an amount of 0.5 to 2% by weight. If desired, the composition according to the invention may further comprise magnesium stearate, preferably in an amount of 0.1 to 0.5% by weight. According to this aspect, when the amount of said at least one alcohol is not more than 70% by weight, the composition further comprises citric acid in the amount specified above. Where the amount of the at least one alcohol is at least 70% by weight, the inclusion of citric acid is optional. The compositions of the present invention may also optionally include conventional additives such as fillers, lubricants, disintegrants, glidants, flavors, sweeteners, colorants, etc., all of which are known per se. May be contained. Examples of fillers that can be used according to the invention are lactose, starch, microcrystalline cellulose, maltrin and the like. The compositions of the present invention are prepared in a manner known per se, which is well known to the person skilled in the art. For example, the PAI and all other active ingredients (excluding lubricants, if used) are sieved and mixed thoroughly in a suitable granulator. Granulation can be performed in the presence of pure water, followed by drying the composition. Next, the dried granules are crushed, lubricated and compressed into tablets. The R (+) PAI itself can be prepared, for example, according to the method disclosed in Example 6B of WO 95/1 1016. The following non-limiting examples are provided for illustrative purposes. Examples Example 1 mg / tablet R (+) - N- propargyl-1-aminoindan mesylate 3.12 Mannitol 62.5 Maltodextrin (Maltrin 150) 36.0 Croscarmellose sodium (Croscarmellose sodium) (Ac-Di -Sol) 2.1 Talc 1.5 Example 2 mg / tablet R (+)-N-propargyl-1-aminoindane mesylate 1.56 mannitol 79.14 starch 10.0 pregelatinized starch 10.0 colloidal silicon dioxide 0.6 talc 2.0 stearic acid 2.0 example 3 mg / tablet R (+) -N-propargyl-1-aminoindane mesylate 3.12 Mannitol 76.58 Starch 10.0 Pregelatinized starch 10.0 Colloidal silicon dioxide 0.6 Citric acid 1.0 Talc 2.0 Example 4 mg / tablet R (+)-N-propargyl-1-amino Indan mesylate 3.12 Mannitol 69.88 Lactose (including ) 14.0 Starch 14.0 Glyceryl behenate (competent trawl 888ATO) (Glyceryl Behenata) (Compitrol 888ATO) 2.0 Example 5 mg / tablet R (+) - N- propargyl-1-aminoindan mesylate 3.12 Mannitol 77.28 Starch 10.0 Starch STA- RX 1500 10.0 Colloidal Silicon Dioxide, Aerosil 0.6 Hydrogenated Vegetable Type I (Sterotex Drytex) 2.0 Example 6 To compare the composition of the present invention with those known in the prior art, two of the above formulations were used. Compared to the formulation disclosed in WO 95/11016. Formulation of WO95 / 11016 mg / tablet R (+)-N-propargyl-1-aminoindan HCl 1.56 Lactose (water-containing) 50.0 Pregelatinized starch 36.0 Microcrystalline cellulose 14.0 Sodium starch glycolate 2.14 Talc 1.0 Magnesium stearate 0.5 This formulation, and the formulations described in Examples 2 and 3 of this application, were exposed to 40 ° C., 75% humidity for 6 months. The percentage of active ingredient degradants was assayed at the end of the 6 month period. The following procedure was applied to determine the degradation of the prepared formulation. The tablets were ground finely and extracted with a diluent such as a mixture of water, acetonitrile and perchloric acid. An aliquot of the extraction product was injected on HPLC and eluted with a mixture similar to the diluent mixture. The area corresponding to the PAI compound was measured along with any other major peak areas. Calculation of the rate of degradation was performed by comparing the area obtained from the standard preparation with the area of the measured peak. Formulations prepared according to the disclosure of Example 20 of WO 95/11016 contained 3.08% of degradants after storage, whereas the compositions of Examples 2 and 3 had 0.51% and 0.1%, respectively. It contained less than 1% of decomposed products. Example 7 Formulations according to the invention and other formulations according to the description in Example 20 of WO 95/11016 were prepared to contain the components indicated in Table 1. When the formulations shown in this table were prepared in accordance with the disclosure of WO 95/11016, they are designated as "PCT" and the numeric formulations correspond to the numbers in the examples of the described application. The modifiers A, B, C or D appearing after some of these abbreviations represent particular changes in the formulation. The percentage of degradation shown in Table 2 was calculated for all of the formulations in Table 1 after storing them at 75% humidity for 1 month at 55 ° C or 6 months at 40 ° C. These formulations stored according to the latter storage conditions are marked in the table with an asterisk ( * ). As can be seen from Table 2, the stability of all compositions of the present invention is superior to that of the prior art.

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Claims (1)

【特許請求の範囲】 １． 活性成分としてラセミ体、Ｓ（−）、及びＲ（＋）−Ｎ−プロパルギル −１−アミノインダンの群から選択される構成要素である化合物又はこれらの薬 学的に許容しうる塩の治療に効果的な量、及び少なくとも６０重量％の、五価及 び六価アルコールの群から選択される構成要素である少なくとも１つのアルコー ルを含有する薬学的組成物。 ２． 請求の範囲第１項に記載の薬学的組成物であって、少なくとも７０重量 ％の前記の少なくとも１つのアルコールを含有するもの。 ３． 請求の範囲第１項又は２項に記載の薬学的組成物であって、前記の少な くとも１つのアルコールがマンニトール、キシリトール及びソルビトールの群か ら選択される構成要素であるもの。 ４． 請求の範囲第１項から第３項の何れか１項に記載の薬学的組成物であっ て、クエン酸を更に含有するもの。 ５． 請求の範囲第４項に記載の薬学的組成物であって、クエン酸の量が０． ５から２重量％であるもの。 ６． 請求の範囲第１項から第５項の何れか１項に記載の薬学的組成物であっ て、ステアリン酸マグネシウムを更に含有するもの。 ７． 請求の範囲第６項に記載の薬学的組成物であって、ステアリン酸マグネ シウムの量が０．１から０．５重量％であるもの。 ８． 請求の範囲第６項又は７項に記載の薬学的組成物であって、前記の少な くとも１つのアルコールの量が７０％以下であり、クエン酸を更に含有するもの 。 ９． 請求の範囲第１項から第８項の何れか１項に記載の薬学的組成物であっ て、前記活性成分がＲ（＋）−Ｎ−プロパルギル−１−アミノインダンであるも の。[Claims]   1. Racemic, S (-), and R (+)-N-propargyl as active ingredients -1- A compound which is a constituent element selected from the group of aminoindan or a drug for these A therapeutically effective amount of a physiologically acceptable salt, and at least 60% by weight of a pentavalent At least one alcohol selected from the group consisting of A pharmaceutical composition comprising   2. A pharmaceutical composition according to claim 1, wherein the composition is at least 70% by weight. % Of said at least one alcohol.   3. The pharmaceutical composition according to claim 1 or 2, wherein said pharmaceutical composition comprises At least one alcohol is a group of mannitol, xylitol and sorbitol The components that are selected from   4. The pharmaceutical composition according to any one of claims 1 to 3, wherein And further containing citric acid.   5. 5. The pharmaceutical composition according to claim 4, wherein the amount of citric acid is 0. 5 to 2% by weight.   6. The pharmaceutical composition according to any one of claims 1 to 5, wherein And further containing magnesium stearate.   7. 7. The pharmaceutical composition according to claim 6, wherein magnesia stearate is used. Those having an amount of 0.1 to 0.5% by weight.   8. A pharmaceutical composition according to claim 6 or 7, wherein said pharmaceutical composition comprises: The amount of at least one alcohol is 70% or less and further contains citric acid .   9. The pharmaceutical composition according to any one of claims 1 to 8, wherein Wherein the active ingredient is R (+)-N-propargyl-1-aminoindan of.
JP51411997A 1995-09-20 1996-09-18 Stable composition containing N-propargyl-1-aminoindan Expired - Lifetime JP4108750B2 (en)

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US6126968A (en) 2000-10-03
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